Promise for prostatitis?


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The simple and honest answer to this is almost certainly no. Many of the assumptions underlying this conclusion are similar to the ones for interstitial cystitis, which were reviewed last month [1]. For example, we are dealing with a symptom complex, there is no guaranteed regulatory route for approval, and little is known about the pathophysiology of the disorder; but despite the considerable medical need, the pharmaceutical industry has not committed any degree of R&D resource to this area. Is it likely that industry will change their views on this? Probably not, as they will look at the potential return on their investment as being relatively modest.

In this respect, the situation is worse than that for interstitial cystitis, where, at least within some of the smaller companies, there is a modicum of de novo research activity. One would like to think that a more scientific approach will eventually develop rather than that which has resulted in the current ‘market leader’, quoted as: “. . . clinically shown to have antioxidant, anti-inflammatory and anti-microbial properties. Our proprietary blend of specially formulated bioflavonoids are naturally found in red wine, onions, green tea and other natural substances”. As someone who used to market α-blockers I certainly applaud the distributors ability to weave into their claim that “bioflavonoids have also been shown to be effective versus prostate cancer”; and all this for $1.30 a day, which is a pricing premium, incidentally, over most generic α-blockers.

However, on a more serious note there is an investment in clinical evaluation led by the NIH/NIDDK in the USA. Before starting the study there were several anecdotal clinical reports that a veritable miscellany of agents could produce modest relief of some of the symptoms of prostatitis when used as monotherapy, particularly drugs effective in the treatment of BPH and those with antimicrobial properties. To add some degree of rigour, a large NIH-sponsored multicentre study is evaluating the hypothesis that a combination of an antibiotic and an α-blocker could be effective across the prostate-based symptom-complex observed in the ‘typical’ patient. However, I am not entirely convinced that the large cohort of patients with prostatitis and co-morbid sexual dysfunction will necessarily appreciate the impact of the designated α-blocker, tamsulosin, on their overall quality of life. Furthermore, given the product attributes of the leader in the prostatitis marketplace (described above), a trial of a chemically defined brand of Serenoa repens (e.g. Permixon) might have equal scientific justification! At this juncture, it might be safest to assume that, short of the ‘great white hopes’ of gene therapy and stem-cell research, the scope for developing novel therapy for prostatitis may have been exhausted. At least the pharmaceutical industry can be proud of their achievements in the treatment of the other prostatic diseases, i.e. LUTS associated with BPH and prostatic carcinoma. Or can they?

Looking first at prostate cancer, how successful has drug therapy been? There is no doubt that androgen-ablation-based strategies show important changes in clinical surrogate endpoints such as PSA velocity and even disease-free progression. The evidence for a consistent improvement in patient survival is much less convincing with the use of these drugs as monotherapy or combined with drugs designed to suppress hormone-refractory carcinoma. Although none of this should detract from the considerable degree of clinical benefit that many patients achieve on such therapies, one is left with the impression that the task is not completed. Whether the solution is in the hands of the classical pharmaceutical industry (e.g. with endothelin antagonists such as atrasentan) or the biotechnologists (gene therapists and stem cell biologists), remains to be seen. The deciding factor, in terms of the development of novel strategies for treating carcinoma, will be the cost of the studies. Patient survival is a straightforward outcome to measure but to prove a change in this variable requires large studies (estimated at 17 000 patients to be followed for at least 7 years). This may well be outside the scope of any company unless supported by government funding.

In BPH we have the situation where the medical management predominantly involves the use of α-blockers which collectively have sales in excess of $2.5 billion/year. This would indicate that there is good patient satisfaction and/or compliance. However, it is now reasonably well documented that about a third of patients with BPH do not respond to α-blockers, about a third have some response and then stop (either completely or proceed to surgery at some time) and only the remaining third have a sustained benefit. One would like to assume that these patients return to ‘normal’. We know from the elegant work of Mike Barry that a 3-point change in the IPSS is noticeable by patients. The clinical trials data for α-blockers shows a median increase of 2–3 IPSS units, which is consistent with the picture presented above (spectrum between no and full response). However, this does not imply that many of these patients, although they may be satisfied, are actually ‘normalised’. Although this type of analysis is rarely conducted (or at least published), given the documented inclusion/exclusion criteria, patient normalisation would require a change of 7–12 IPSS points; this is not routinely observed. This could in theory be achieved by adding a second pharmacological agent (e.g. an antimuscarinic or neurokinin antagonist), but there may well be implications in terms of both side-effects and cost.

A perceived limitation of α-blocker therapy is that the disease progression is ongoing and such therapy has been described as ‘surgical Elastoplast (Band-aid)’. This has led to some degree of combined therapy using α-blockers with 5α-reductase inhibitors. There is compelling clinical evidence that this results in both acute symptom relief and a reduction in the clinical manifestation of disease progression. Although the apparent clinical impact based on the percentage change in patients requiring surgical intervention or catheterization is high, the absolute number of patients affected is small. Given the obvious negative cost implications in terms of drug supply it is not clear that combined therapy will be acceptable to the healthcare provider, be it physician, the patient or insurance company. Therefore, the situation in BPH would appear to be similar to that in prostate cancer. The situation with respect to therapy for prostatitis is surprisingly similar!

Next month, I will predict the great advances likely to be forthcoming in 2006.